Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases
Abstract
Papillon-Lefevre syndrome (PLS) is characterized by nonfunctional neutrophil serine proteases (NSPs) and fulminant periodontal inflammation of unknown cause. Here we investigated neutrophil extracellular trap (NET)-associated aggregation and cytokine/chemokine-release/degradation by normal and NSP-deficient human and mouse granulocytes.
Stimulated with solid or soluble NET inducers, normal neutrophils formed aggregates and both released and degraded cytokines/chemokines. With increasing cell density, proteolytic degradation outweighed release.
Maximum output of cytokines/chemokines occurred mostly at densities between 2 x 10(7) and 4 x 10(7) neutrophils/cm(3). Assessment of neutrophil density in vivo showed that these concentrations are surpassed during inflammation.
Association with aggregated NETs conferred protection of neutrophil elastase against 1-antitrypsin. In contrast, eosinophils did not influence cytokine/chemokine concentrations.
The proteolytic degradation of inflammatory mediators seen in NETs was abrogated in Papillon-Lefevre syndrome (PLS) neutrophils. In summary, neutrophil-driven proteolysis of inflammatory mediators works as a built-in safeguard for inflammation.
The absence of this negative feedback mechanism might be responsible for the nonresolving periodontitis seen in PLS.